1. Field of the Invention
This invention relates to hyperproliferative and inflammatory disorders of the skin, especially to new methods for inhibiting proliferation of keratinocytes and for treating hyperproliferative and inflammatory disorders of the skin including psoriasis and acne vulgaris.
2. Background
Abnormal cell proliferation and inflammation are key features of a number of disorders of the skin. For example, hyperproliferation of keratinocytes is a key feature of psoriasis, a disease of the skin which produces inflammatory lesions that are thickened, scaling, and non-scarring. Psoriasis affects about 1-2% of the United States population with an incidence of about 200,000 new cases per year. Hyperproliferation of keratinocytes and inflammation of the skin are also key features of acne vulgaris, a disorder that produces comedones and the potential for scarring lesions and cysts. Acne is a very common disorder particularly among teenagers. For example, acne has been reported to affect as many 35 percent of males and 41 percent of females between the ages of 15 and 19.
Nuclear hormone receptors are intracellular receptors that influence the expression of genes involved in cell proliferation and inflammation. Nuclear hormone receptors present in skin play a key role in the proliferative and inflammatory changes that contribute to psoriasis, acne vulgaris, and other hyperproliferative and inflammatory disorders of the skin. Examples of nuclear hormone receptors known to be present in skin include the vitamin D receptor, the retinoic acid receptor, and the steroid receptor.
It has been reported that some nuclear hormone receptors are not expressed in mammalian skin. For example, the prior art indicates that mammalian keratinocytes do not express any nucleic acid message encoding the peroxisome proliferator activated receptor gamma (PPAR.gamma.), a member of the Class II family of nuclear hormone receptors. The term PPAR.gamma. is used here and throughout this entire writing to mean either the .gamma..sub.1 or .gamma..sub.2 subtypes or both.
Compounds that modify the activity of nuclear hormone receptors present in skin are known to be useful for inhibiting proliferation of keratinocytes and treating hyperproliferative and inflammatory disorders of the skin such as psoriasis and acne vulgaris. For example, the retinoic acid receptor is a member of the Class II family of nuclear hormone receptors that is expressed in keratinocytes and plays an important role in cell proliferation and inflammation and various disorders including acne vulgaris and psoriasis. Drugs such as etretinate or all-trans retinoic acid that modify the activity of retinoid receptors have proven to be useful for inhibiting hyperproliferation of keratinocytes and for treatment of a variety of hyperproliferative and inflammatory skin diseases including acne vulgaris and psoriasis.
The vitamin D receptor is a member of the Class II family of nuclear hormone receptors that is also expressed in keratinocytes; drugs that modify the activity of the vitamin D receptor in keratinocytes have also been found to be useful for inhibiting proliferation of keratinocytes and for treating psoriasis. Steroid receptors also belong to the superfamily of nuclear hormone receptors and are expressed in skin. Corticosteroids, when administered systemically or topically, have proven to be useful for treating hyperproliferative and inflammatory disorders of the skin including psoriasis and acne vulgaris.
Because the prior art clearly indicates that PPAR.gamma. is not present in mammalian keratinocytes, those skilled in the art would not expect compounds that modify the activity of this nuclear receptor to be useful for inhibiting the proliferation of keratinocytes or for treating hyperproliferative or inflammatory disorders of the skin.
Thiazolidinediones are known to have a variety of cellular effects including modifying calcium channel activity, modifying protein kinase activity, and modifying the activity of the peroxisome proliferator activated receptor gamma in various tissues other than skin. Thiazolidinediones inhibit the proliferation of keratinocytes and are useful for treating psoriasis but these effects are not suspected by those skilled in the art to involve modifying the activity of PPAR.gamma.. Because the prior art indicates that PPAR.gamma. is not present in mammalian keratinocytes, those skilled in the art would not expect other compounds that modify the activity of this nuclear receptor to be useful for inhibiting the proliferation of keratinocytes or for treating hyperproliferative or inflammatory disorders of the skin.
Although a number of compounds that modify the activity of nuclear hormone receptors present in skin can be used to inhibit proliferation of keratinocytes and to treat hyperproliferative, inflammatory disorders of the skin, they are accompanied by a variety of side effects and are not effective in all patients. For example, retinoids are known to treat ogens and can have a broad range of side effects including irritation of the skin and disturbances in lipid metabolism. Vitamin D compounds can cause hypercalcemia and hypercalciuria and only 25%-50% of patients with psoriasis show substantial clinical improvement in response to therapy with vitamin D compounds. Corticosteroids are often effective in reducing hyperproliferative and inflammatory changes of the skin but chronic topical use of corticosteroids can lead to thinning of the skin, development of resistance to therapy, and loss of efficacy. Oral administration of corticosteroids is associated with a number of serious side effects including adrenal insufficiency, hypertension, osteoporosis, and immunosuppression.
Although other therapies exist for hyperproliferative and inflammatory disorders of the skin that do involve compounds that directly modify activity of nuclear hormone receptors, such alternative therapies are not uniformly effective and are accompanied by a variety of side effects that are at best unpleasant and often dangerous. For instance, tar based therapies are uncomfortable and a nuisance to apply. Immunosuppressants such as methotrexate can predispose to malignancy, cyclosporine can cause renal damage and hypertension, and psoralens and ultraviolet light therapy can increase the risk for cancers of the skin.
Because of the distressing and disfiguring nature of hyperproliferative and inflammatory disorders of the skin including psoriasis and acne vulgaris, as well as the unsatisfactory aspects of current therapies, there is considerable interest in developing new methods of inhibiting proliferation of keratinocytes and treating hyperproliferative and inflammatory disorders of the skin.